There is currently considerable interest in the genetics of osteoporosis. One tool in genetic studies is the inbred rat model. We have identified an inbred strain of rats (Fischer 344) that has lower bone mineral density (BMD) and more fragile bones than several other rat strains. Compared to Lewis rats, adult, female Fischer rats has 12-14% less bone mineral density, 30% more brittleness at the femoral midshaft and 40% less work in fracture in the femur and lumbar vertebra. The Fischer rats are also different than the Lewis rats in femoral and vertebral geometry. Fischer and Lewis strains are among the rat lines screened for microsatellite markers, making it possible to use the quantitative trait loci approach to identify chromosomal regions that affect bone fragility. We hypothesize that 1) chromosomal regions harboring genes that regulate femoral and vertebral fragility, BMD, and geometry can be determined for rats; 2) skeletal fragility, BMD, and geometry are regulated, at least in part, by different genetic loci; and 3) Fischer 344 and Lewis rats are different in their skeletal biology. We propose studies to numerate genes that regulate bone mineral density (BMD), fragility and geometry in Fischer and Lewis rats. Fischer 344 and Lewis progenitor rats will be mated and their F1 hybrid offspring intercrossed to create an F2 population containing 500- 600 individuals. These rats will be phenotyped based upon BMD (Aim 1), biomechanical properties (Aim 2), or skeletal geometry (Aim 3). Quantitative trait loci (QTL) analyses will be performed to identify the genetic loci influencing variation in the skeletal phenotypes. In addition we will further characterize the Fischer and Lewis rat strains to determine if a) bone remodeling rates are different in the two strains, b) their bones will respond differently to ovariectomy, and c) their skeletons will respond differently to mechanical loading.